This invention relates to compositions useful in the preparation of stable scintigraphic scanning (or, "radiodiagnostic") agents employing technetium-99m. More particularly, gentisyl alcohol (or soluble gentisyl alcohol compound) is used as a non-interfering stabilizer for such compositions.
Scintigraphy and similar radiographic techniques are finding ever increasing application in biological and medical research and diagnostic procedures. In general, scintigraphy procedures involve the preparation of radioactive scanning agents which, upon introduction into a biological subject, become localized in specific organs, tissue or skeletal material which are under study. When so localized, traces, plots or scintiphotos of the distribution of the radioactive material can be made by various radiation detectors, i.e., such as traversing scanners, scintillation cameras and the like. The resultant distribution and corresponding relative intensities can then be used to indicate the position occupied by the tissue in which the radionuclide is localized as well as indicate the presence of aberrations, pathological conditions, and the like.
In general, and depending on the type of radionuclide used and the organ of interest, a scintigraphic scanning agent as used in the hospital comprises a radionuclide, a carrier agent designed to target the specific organ, various auxiliary agents which affix the radionuclide to the carrier, water or other delivery vehicle suitable for injection into, or aspiration by, the patient, physiologic buffers and salts, and the like.
Technetium-99m is a radionuclide which is widely known for use in tissue scanning agents. This radionuclide is conveniently available from commercial pertechnetate sources.
Pertechnetate is in the +7 oxidation state, which is too high to be used in the preparation of scanning agents such as those used for bone mineral and lung. This problem is easily overcome by reducing the pertechnetate to what is believed to be the +3, +4 and/or +5 oxidation state.
In general, .sup.99m Tc-labeled scanning agents are prepared by admixing a pertechnetate-99m isotonic saline solution with a pertechnetate reducing agent such as the stannous, ferrous or chromous salt of sulfuric or hydrochloric acid, and the desired carrier agent for targeting the organ of interest. For example, U.S. Pat. No. 3,983,227, Tofe and Francis, discloses the use of reducing salts with radioactive pertechnetate solutions and organophosphonate bone-seeking carriers to prepare bone scanning agents. U.S. Pat. No. 4,002,730, Tofe, Hartman and Kretschmar, describes .sup.99m Tc lung scanning agents prepared by mixing a pertechnetate solution from commercial generators with stannous/starch particles which provide a combined reducing agent/carrier.
While such procedures provide scanning agents which are superior to those previously available, they have shortcomings. Most notably, it has been found that conventional technetium-containing scintigraphic scanning agents are unstable in the presence of oxygen and radiolysis products. Accordingly, previously-described technetium-based scanning agents have been made oxygen-free by saturating the composition with oxygen-free nitrogen gas or by preparing the agent in an oxygen-free atmosphere or in a vacuum. However, even such painstaking precautionary procedures are not entirely satisfactory, since it is extremely difficult to maintain oxygen-free conditions. For instance, pertechnetate solutions may contain dissolved oxygen which, if not detected prior to combination with the pertechnetate reducing agent, forms a product which is unstable and results in the undesirable formation of free pertechnetate-99m.
Others have disclosed means for overcoming the aforesaid instability problem using chemical stabilizers. German Offenlegungsschrift No. 2,618,337, Tofe, published Nov. 11, 1976, discloses the use of ascorbate stabilizers with technetium scanning agents. U.S. Pat. No. 4,075,314, issued Feb. 21, 1978, discloses the use of ascorbate to inhibit the oxidation of Sn.sup.+2 and to inhibit the reoxidation of reduced technetium in a pyrophosphate-based bone scanning agent.
It has now been discovered that gentisyl alcohol compounds are safe, effective, and non-interfering stabilizers for scanning agents used in the radiographic diagnosis of tissues (including bone mineral) of humans and lower animals.
The co-pending application of the invention herein, Ser. No. 892,245, filed Mar. 31, 1978, entitled STABILIZED RADIOGRAPHIC SCANNING AGENTS discloses the use of gentisic acid in radiodiagnostic compositions.
The concurrently-filed application of Whitehouse, Ser. No. 920,081, filed June 28, 1978, entitled RADIOACTIVE SCANNING AGENTS WITH HYDROQUINONE STABILIZER teaches the use of hydroquinone in radiodiagnostic compositions.